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Treatment of KRAS G12C Mutation

This is Part 3 of Appropriate Management of Challenging Cases in Lung Cancer, a five-part video roundtable series. Scroll down to watch the other videos from this Roundtable.

Drs. Ramalingam, Brahmer, and Wakelee review the role of KRAS G12C mutation in lung cancer, which is found is 13% of all non–small cell lung cancer. They highlight two investigational therapies, AMG 510 and MRTX 849, and discuss recently presented data.


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Transcript

DR. RAMALINGAM: Hello. Welcome to The ASCO Post Roundtable Series on the Appropriate Management of Challenging Cases in Lung Cancer. I'm Dr. Suresh Ramalingam, Deputy Director of the Winship Cancer Institute of Emory University. Today I'm joined by two of my esteemed colleagues in thoracic oncology, Dr. Julie Brahmer and Dr. Heather Wakelee. DR. BRAHMER: Hi, I'm Dr. Julie Brahmer. I’m a professor of oncology from the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland. DR. WAKELEE: Hi, I'm Dr. Heather Wakelee, professor of medicine in the Division of Oncology at Stanford University. DR. RAMALINGAM: Thank you for joining us. Today we will be discussing a very exciting topic, which is KRAS G12C mutation in lung cancer. Julie, KRAS mutations account for almost 25% of lung adenocarcinomas, and now that we're doing NGS, or next-generation sequencing, testing for all patient with metastatic non-squamous lung cancer, we're going to be able to know who has the KRAS mutations. For almost 20, 30 years, we've tried to develop targeted therapies for KRAS mutations, and there has not been much success to show for it. But it seems to be that we're turning the corner on that. We've seen two drugs that have shown some interesting early data. Let me ask you to talk to us about G12C mutation. What's the prevalence? What’s unique about it? DR. BRAHMER: All right. So, not all KRAS mutations are the same, and so there's various different mutations, and what we're going to talk about today is the KRAS G12C, which accounts for about 13% of non–small cell lung cancers. So certainly of all the different KRAS mutations, this is prevalent. However, when you're looking at the NGS report, you do have to pay attention to which KRAS mutation your patient has. So for patients with KRAS G12C, what this mutation does, this mutant cysteine actually changes and creates a binding pocket. And by using some of these drugs, so this allows the development of a targeted drug that actually can bind to this pocket and create, or inactivate, this and block the oncogenic signaling through this pathway. So this is the uniqueness of these type of inhibitors, and again, it's specific right now for just patients with KRAS G12C. I think some of the data that's come out over the past year is certainly very exciting, and finally seeing this tough nut starting to crack. I don't think that we have all the information that we need. However, I think based on some of the early data from the phase I study that has looked at the AMG 510 drug as well as others, is showing that particularly in non–small cell lung cancer, response rates based on a small number of patients, at least with the AMG 510, is roughly 48%. So again, for patients where they never had a tyrosine kinase inhibitor option, this certainly is tantalizing. I think what we need to see is the duration of those responses. How long do those responses last? Are we talking osimertinib-like length of time, or alectinib length of time for those other driver mutations? We shall see. I think the disease control rate, also the AMG 510 drug of nearly – almost 100% based on some of the data that came out of ASCO in 2019, as well as World Lung Cancer Congress in 2019, and then also ESMO. Again, for these patients it's quite interesting, but again, it's only for patients with KRAS G12C. In general at least, this drug was pretty easy to tolerate. The main side effect was some GI toxicities, but again, those were typically low grade. So for this patient population, this is exciting. Now, this is not the only drug now in this class. MRTX 849—that drug was presented in October 2019. But that data was quite small: only six patients with non–small cell lung cancer had evaluable disease, and three of six, though, did have a response. And we hope to see over the next year even more data with this drug, as well as others in this class. Heather, anything to add? DR. WAKELEE: That was a great summary, Julie. I think one of the important points – we've gotten used to thinking about when we find a driver mutation, and we have a targeted agent, we now know for several of those, especially EGFR and ALK, the ones we think about the most, that when you find that driver mutation, you want to start with a targeted treatment versus chemotherapy. We've got lots of randomized phase III data to tell us that. We also know that the immune checkpoint inhibitors, at least alone, don't have a very high activity rate with EGFR, with ALK, with ROS1, with RET, with several of those driver mutations where we have great targeted drugs. But the story in KRAS is more complicated, because we know that with KRAS, actually immune checkpoint inhibitor responses are good, for the most part. And so I think it's important to emphasize that when you find a KRAS mutation, first line, you probably still want to be thinking about chemotherapy with immune therapy, or even immune checkpoint inhibitor therapy alone, and then these drugs are going to come in in the second line, at least for now. If in the end, the disease-free survival with these is quite good, which early data isn't necessarily looking quite as great as we see with some of the other drugs, but again it's later lines of treatment, so we don't really know, that story might change. But at least for now, when I think about KRAS, I still think about immune therapy with or without chemotherapy first line, and then it's exciting that we have these drugs becoming available, still in trials, but eventually should be out there as another option, because we do see KRAS patients a lot. And it is frustrating when you see patients with the other KRAS mutations, knowing that we don't have targeted agents yet. But as it's been explained to me that that cysteine residue is what's critical for the mechanism of action of the drugs that we do have. And as we continue to delve into the other mutations that will be a little trickier to target. Hopefully we'll end up with some options or combination regimens that will work for them. DR. RAMALINGAM: Yes, the combination piece is critical, Heather. As you know for, for BRAF-mutated patients, we use a combination approach. Direct targeting of RAF alone has a response rate of 20 to 30%, but when you combine it with a MEK inhibitor, with dabrafenib/trametinib combination in lung cancer, it has a response rate of over 60%, and the median PFS is about 13, 14 months. So these exciting developments in the G12C arena are in later lines of therapy, as you rightly point out. So, we will obviously have to study them in a frontline setting for metastatic disease and see where the numbers shake out. And it may well be that we will build on these to bring about novel combination approaches. What do you think are the next steps? What kind of data are you anticipating with these agents in the next few months, Julie? DR. BRAHMER: I think just, you know, updates. I think it certainly would be great to be able to see some of the expansion cohort data. I think most importantly, again, we're all waiting for duration of response data. And then also, what are the mechanisms of resistance, and then that will drive the different combinations. Clearly, there are trials that are looking at different combinations to try to block this pathway even more permanently, and we'll see how patients can tolerate those combinations as well. DR. RAMALINGAM: The good news is, there are a number of ongoing trials with KRAS G12C inhibitors, especially combination trials. There are also some phase III trials that are kicking off to look at it in the salvage therapy setting for metastatic non–small cell lung cancer. And so a very exciting time. The key takeaways that I take from this conversation are, number one, KRAS G12C mutations are common in lung cancer, 13% of all cases of non–small cell lung cancer. Number two, the direct KRAS G12C inhibitors, AMG [510] and the MRTX [849] drugs, both have shown early promise in terms of response rates, disease control rate. We await the PFS data and long-term follow-up in larger groups of patients. But clearly, I would encourage our audience to look out for these mutations in their patients, and if you do see them, you may want to consider them for a clinical trial that involves a direct KRAS G12C mutation. So with that, we'll wrap up. I want to thank both Drs. Wakelee and Brahmer for joining us today. I want to thank you, our audience, for watching us in this program, and also to remind you to watch other videos in The ASCO Post Roundtable Series. Thank you very much.
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